Glucagon-like peptide 1 receptor (GLP-1R) belongs to Family B1 of the seven-transmembrane G protein-coupled receptors, and its natural agonist ligand is the peptide hormone glucagon-like peptide-1 (GLP-1). GLP-1 is a peptide hormone arising by its alternative enzymatic cleavage from proglucagon, the prohormone precursor for GLP-1, which is highly expressed in enteroendocrine cells of the intestine, the alpha cells of the endocrine pancreas (islets of Langerhans), and the brain (Kieffer T. J. and Habener, J. F. Endocrin. Rev. 20:876-913 (1999); Drucker, D. J., Endocrinology 142:521-7 (2001); Holst, J. J., Diabetes Metab. Res. Rev. 18:430-41 (2002)). The initial actions of GLP-1 observed were on the insulin-producing cells of the islets, where it stimulates glucose-dependent insulin secretion. Subsequently, multiple additional antidiabetogenic actions of GLP-1 were discovered including the stimulation of the growth and inhibition of the apoptosis of pancreatic beta cells (Drucker, D. J., Endocrinology 144:5145-8 (2003); Holz, G. G. and Chepurny O. G., Curr. Med. Chem. 10:2471-83 (2003); List, J. F. and Habener, J. F., Am. J. Physiol. Endocrinol. Metab. 286:E875-81 (2004)).
On activation, GLP-1 receptors couple to the a subunit of G protein, with subsequent activation of adenylate cyclase and increase of cAMP levels, thereby potentiating glucose-stimulated insulin secretion. Therefore, GLP-1 is an attractive therapeutic to lower blood glucose and preserve the β-cells of the pancreas of diabetic patients. Glucagon has been used for decades in medical practice within diabetes and several glucagon-like peptides are being developed for various therapeutic indications. GLP-1 analogs and derivatives are being developed for the treatment for patients suffering from diabetes.
As it has been well established in the field of protein crystallography that the monodispersity of protein samples is a major determinant of success in crystallization, development of compounds that are capable of maintaining the GLP-1 receptor in a monodisperse, functional state throughout purification, concentration and crystallization trials is a crucial preliminary step in the structural determination effort of the GLP-1 receptor. Disclosed herein are compounds that are capable of inducing such stabilizing effects on the GLP-1 receptor. The compounds of the disclosure are screened for their ability to support structural determination of the GLP-1 receptor to high resolution, thus allowing an additional dimension of diversity in crystallization. The compounds of the disclosure enable drug development through the structural solution of clinically relevant GPCR targets. Structural coordinates can be leveraged as a discovery platform for generating novel chemical leads through virtual ligand screening followed by in vitro screening and chemical optimization of hits for standard drug-like properties and efficacy. In addition, it is well known in the field of structural biology that the initial structural solution of a given target enables subsequent structures with less favorable ligands due to the growth in knowledge and restriction of crystallization space that must be screened.